A pro‐survival role for the intracellular granzyme B inhibitor Serpinb9 in natural killer cells during poxvirus infection

Mangan, Matthew; Melo‐Silva, Carolina R.; Luu, Jennii; Bird, Catherina H.; Koskinen, Aulikki; Rizzitelli, Alexandra; Prakash, Monica D.; Scarff, Katrina Louise; Müllbacher, Arno; Regner, Matthias; Bird, Phillip I.

doi:10.1038/icb.2017.59

Cited by 23 publications

(17 citation statements)

References 50 publications

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“…NK cells induce apoptosis in virus‐infected host cells by producing cytotoxic granzyme B in a mechanism regulated by the endogenous cytosolic granzyme B inhibitor serpinB9 5 . Mangan et al (④ in Figure 1) describe the importance of serpinB9 in enhancing cytotoxic killing by NK cells early in viral infections, and later, by CD8 + T cells 6 …”

Section: Figurementioning

confidence: 99%

COVID‐19: searching for clues among other respiratory viruses

et al. 2020

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Section: Figurementioning

confidence: 99%

COVID‐19: searching for clues among other respiratory viruses

et al. 2020

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“…In cytolytic CD8 cells and NK cells, powerful granule serine proteases that are regulated by endogenous inhibitors called serpins play pivotal roles in immune surveillance against tumors and viral infection while simultaneously maintaining immune homeostasis (19)(20)(21)(22)(23)(24)(25)(26). Whether analogous granzyme-serpin regulation exists in CD4 cells is not known.…”

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SerpinB1 controls encephalitogenic T helper cells in neuroinflammation

Hou

Rao

Yuki

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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SerpinB1, a protease inhibitor and neutrophil survival factor, was recently linked with IL-17–expressing T cells. Here, we show that serpinB1 (Sb1) is dramatically induced in a subset of effector CD4 cells in experimental autoimmune encephalomyelitis (EAE). Despite normal T cell priming, Sb1−/− mice are resistant to EAE with a paucity of T helper (TH) cells that produce two or more of the cytokines, IFNγ, GM-CSF, and IL-17. These multiple cytokine-producing CD4 cells proliferate extremely rapidly; highly express the cytolytic granule proteins perforin-A, granzyme C (GzmC), and GzmA and surface receptors IL-23R, IL-7Rα, and IL-1R1; and can be identified by the surface marker CXCR6. In Sb1−/− mice, CXCR6+ TH cells are generated but fail to expand due to enhanced granule protease-mediated mitochondrial damage leading to suicidal cell death. Finally, anti-CXCR6 antibody treatment, like Sb1 deletion, dramatically reverts EAE, strongly indicating that the CXCR6+ T cells are the drivers of encephalitis.

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“…Cishdeficient NK cells show differential upregulated expression of the gene Serpinb9. Serpinb9 prevents cell death by inactivating proteases such as granzyme B that are released into the host cell interior (49). This suggests a mechanism by which Cishdeficient NK cells harbor an increased killing frequency when they encounter tumor metastases in vivo.…”

Section: Discussionmentioning

confidence: 99%

NK Cell Priming From Endogenous Homeostatic Signals Is Modulated by CIS

et al. 2020

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Natural killer (NK) cell activation is controlled by a balance of activating and inhibitory signals and cytokines such as IL-15. We previously identified cytokine-inducible SH2-containing protein (CIS) as a negative regulator of IL-15 signaling in NK cells under inflammatory conditions. While the functional effect of Cish-deficiency in NK cells was obvious by their increased anti-tumor immunity and hyper-proliferative response to IL-15, it remained unclear how CIS regulates NK cell biology in steady-state. Here, we investigated the role of CIS in the homeostatic maintenance of NK cells and found CIS-ablation promoted terminal differentiation of NK cells and increased turnover, suggesting that under steady-state conditions, CIS plays a role in maintaining IL-15 driven regulation of NK cells in vivo. However, hyper-responsiveness to IL-15 did not manifest in NK cell accumulation, even when the essential NK cell apoptosis mediator, Bcl2l11 (BIM) was deleted in addition to Cish. Instead, loss of CIS conferred a lower activation threshold, evidenced by augmented functionality on a per cell basis both in vitro and in vivo without prior priming. We conclude that Cish regulates IL-15 signaling in NK cells in vivo, and through the rewiring of several activation pathways leads to a reduction in activation threshold, decreasing the requirement for priming and improving NK cell anti-tumor function. Furthermore, this study highlights the tight regulation of NK cell homeostasis by several pathways which prevent NK cell accumulation when IL-15 signaling and intrinsic apoptosis are dysregulated.

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A pro‐survival role for the intracellular granzyme B inhibitor Serpinb9 in natural killer cells during poxvirus infection

Cited by 23 publications

References 50 publications

COVID‐19: searching for clues among other respiratory viruses

COVID‐19: searching for clues among other respiratory viruses

SerpinB1 controls encephalitogenic T helper cells in neuroinflammation

NK Cell Priming From Endogenous Homeostatic Signals Is Modulated by CIS

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